A Bifunctional MAPK/PI3K Antagonist for Inhibition of Tumor Growth and Metastasis
Responses to targeted therapies frequently are brief, with patients relapsing with drug-resistant tumors. For oncogenic MEK and BRAF inhibition, drug resistance commonly occurs through activation of PI3K/AKT/mTOR signaling and immune checkpoint modulation, providing a robust molecular target for con...
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| Veröffentlicht in: | Molecular cancer therapeutics 2017-11, Vol.16 (11), p.2340-2350 |
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| container_title | Molecular cancer therapeutics |
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| creator | Galbán, Stefanie Apfelbaum, April A Espinoza, Carlos Heist, Kevin Haley, Henry Bedi, Karan Ljungman, Mats Galbán, Craig J Luker, Gary D Dort, Marcian Van Ross, Brian D |
| description | Responses to targeted therapies frequently are brief, with patients relapsing with drug-resistant tumors. For oncogenic MEK and BRAF inhibition, drug resistance commonly occurs through activation of PI3K/AKT/mTOR signaling and immune checkpoint modulation, providing a robust molecular target for concomitant therapy. Here, we evaluated the efficacy of a bifunctional kinase inhibitor (ST-162) that concurrently targets MAPK and PI3K signaling pathways. Treatment with ST-162 produced regression of mutant KRAS- or BRAF-addicted xenograft models of colorectal cancer and melanoma and stasis of BRAF/PTEN-mutant melanomas. Combining ST-162 with immune checkpoint blockers further increased efficacy in a syngeneic KRAS-mutant colorectal cancer model. Nascent transcriptome analysis revealed a unique gene set regulated by ST-162 related to melanoma metastasis. Subsequent mouse studies revealed ST-162 was a potent inhibitor of melanoma metastasis to the liver. These findings highlight the significant potential of a single molecule with multikinase activity to achieve tumor control, overcome resistance, and prevent metastases through modulation of interconnected cell signaling pathways.
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| doi_str_mv | 10.1158/1535-7163.MCT-17-0207 |
| format | Article |
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.</description><identifier>ISSN: 1535-7163</identifier><identifier>EISSN: 1538-8514</identifier><identifier>DOI: 10.1158/1535-7163.MCT-17-0207</identifier><identifier>PMID: 28775144</identifier><language>eng</language><publisher>United States: American Association for Cancer Research Inc</publisher><subject>1-Phosphatidylinositol 3-kinase ; AKT protein ; Animal models ; Cancer ; Colorectal cancer ; Colorectal carcinoma ; Drug resistance ; Enzyme inhibitors ; Gene expression ; Immune checkpoint ; Inhibition ; Inhibitors ; K-Ras protein ; Kinases ; Liver ; MAP kinase ; Melanoma ; Metastases ; Metastasis ; Modulation ; PTEN protein ; Regression analysis ; Signal transduction ; Signaling ; TOR protein ; Tumors ; Xenografts</subject><ispartof>Molecular cancer therapeutics, 2017-11, Vol.16 (11), p.2340-2350</ispartof><rights>2017 American Association for Cancer Research.</rights><rights>Copyright American Association for Cancer Research Inc Nov 2017</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c439t-c1cb9c9552e142cd542dd236d185e6c690d9d52c30f6da46c8be2fe7baefbe173</citedby><cites>FETCH-LOGICAL-c439t-c1cb9c9552e142cd542dd236d185e6c690d9d52c30f6da46c8be2fe7baefbe173</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,3343,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28775144$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Galbán, Stefanie</creatorcontrib><creatorcontrib>Apfelbaum, April A</creatorcontrib><creatorcontrib>Espinoza, Carlos</creatorcontrib><creatorcontrib>Heist, Kevin</creatorcontrib><creatorcontrib>Haley, Henry</creatorcontrib><creatorcontrib>Bedi, Karan</creatorcontrib><creatorcontrib>Ljungman, Mats</creatorcontrib><creatorcontrib>Galbán, Craig J</creatorcontrib><creatorcontrib>Luker, Gary D</creatorcontrib><creatorcontrib>Dort, Marcian Van</creatorcontrib><creatorcontrib>Ross, Brian D</creatorcontrib><title>A Bifunctional MAPK/PI3K Antagonist for Inhibition of Tumor Growth and Metastasis</title><title>Molecular cancer therapeutics</title><addtitle>Mol Cancer Ther</addtitle><description>Responses to targeted therapies frequently are brief, with patients relapsing with drug-resistant tumors. For oncogenic MEK and BRAF inhibition, drug resistance commonly occurs through activation of PI3K/AKT/mTOR signaling and immune checkpoint modulation, providing a robust molecular target for concomitant therapy. Here, we evaluated the efficacy of a bifunctional kinase inhibitor (ST-162) that concurrently targets MAPK and PI3K signaling pathways. Treatment with ST-162 produced regression of mutant KRAS- or BRAF-addicted xenograft models of colorectal cancer and melanoma and stasis of BRAF/PTEN-mutant melanomas. Combining ST-162 with immune checkpoint blockers further increased efficacy in a syngeneic KRAS-mutant colorectal cancer model. Nascent transcriptome analysis revealed a unique gene set regulated by ST-162 related to melanoma metastasis. Subsequent mouse studies revealed ST-162 was a potent inhibitor of melanoma metastasis to the liver. These findings highlight the significant potential of a single molecule with multikinase activity to achieve tumor control, overcome resistance, and prevent metastases through modulation of interconnected cell signaling pathways.
.</description><subject>1-Phosphatidylinositol 3-kinase</subject><subject>AKT protein</subject><subject>Animal models</subject><subject>Cancer</subject><subject>Colorectal cancer</subject><subject>Colorectal carcinoma</subject><subject>Drug resistance</subject><subject>Enzyme inhibitors</subject><subject>Gene expression</subject><subject>Immune checkpoint</subject><subject>Inhibition</subject><subject>Inhibitors</subject><subject>K-Ras protein</subject><subject>Kinases</subject><subject>Liver</subject><subject>MAP kinase</subject><subject>Melanoma</subject><subject>Metastases</subject><subject>Metastasis</subject><subject>Modulation</subject><subject>PTEN protein</subject><subject>Regression analysis</subject><subject>Signal transduction</subject><subject>Signaling</subject><subject>TOR protein</subject><subject>Tumors</subject><subject>Xenografts</subject><issn>1535-7163</issn><issn>1538-8514</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><recordid>eNpdkV1PHCEUhompUav9CRqS3vRmdIDh68Zk3bR2oxs12V4TBhgXMwsKM2389zJda6oJCeTwnJePB4BjVJ8iRMUZooRWHDFyupyvKsSrGtd8BxyUuqgERc2nv-stsw8-5_xQ10hIjPbAPhacF6Q5AHczeOG7MZjBx6B7uJzdXp3dLsgVnIVB38fg8wC7mOAirH3rJwrGDq7GTaldpvhnWEMdLFy6QecyfD4Cu53us_vyOh-CXz--r-Y_q-uby8V8dl2ZhsihMsi00khKsUMNNpY22FpMmEWCOmaYrK20FBtSd8zqhhnROtw53mrXtQ5xcgjOt7mPY7tx1rgwJN2rx-Q3Oj2rqL16vxP8Wt3H34oyJgWSJeDba0CKT6PLg9r4bFzf6-DimBWSmDFBeDOd9fUD-hDHVP5rogQRFGNJC0W3lEkx5-S6t8ugWk3S1CRETUJUkaYQV5O00nfy_0veuv5ZIi9RIpM9</recordid><startdate>20171101</startdate><enddate>20171101</enddate><creator>Galbán, Stefanie</creator><creator>Apfelbaum, April A</creator><creator>Espinoza, Carlos</creator><creator>Heist, Kevin</creator><creator>Haley, Henry</creator><creator>Bedi, Karan</creator><creator>Ljungman, Mats</creator><creator>Galbán, Craig J</creator><creator>Luker, Gary D</creator><creator>Dort, Marcian Van</creator><creator>Ross, Brian D</creator><general>American Association for Cancer Research Inc</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QO</scope><scope>7U7</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20171101</creationdate><title>A Bifunctional MAPK/PI3K Antagonist for Inhibition of Tumor Growth and Metastasis</title><author>Galbán, Stefanie ; Apfelbaum, April A ; Espinoza, Carlos ; Heist, Kevin ; Haley, Henry ; Bedi, Karan ; Ljungman, Mats ; Galbán, Craig J ; Luker, Gary D ; Dort, Marcian Van ; Ross, Brian D</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c439t-c1cb9c9552e142cd542dd236d185e6c690d9d52c30f6da46c8be2fe7baefbe173</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>1-Phosphatidylinositol 3-kinase</topic><topic>AKT protein</topic><topic>Animal models</topic><topic>Cancer</topic><topic>Colorectal cancer</topic><topic>Colorectal carcinoma</topic><topic>Drug resistance</topic><topic>Enzyme inhibitors</topic><topic>Gene expression</topic><topic>Immune checkpoint</topic><topic>Inhibition</topic><topic>Inhibitors</topic><topic>K-Ras protein</topic><topic>Kinases</topic><topic>Liver</topic><topic>MAP kinase</topic><topic>Melanoma</topic><topic>Metastases</topic><topic>Metastasis</topic><topic>Modulation</topic><topic>PTEN protein</topic><topic>Regression analysis</topic><topic>Signal transduction</topic><topic>Signaling</topic><topic>TOR protein</topic><topic>Tumors</topic><topic>Xenografts</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Galbán, Stefanie</creatorcontrib><creatorcontrib>Apfelbaum, April A</creatorcontrib><creatorcontrib>Espinoza, Carlos</creatorcontrib><creatorcontrib>Heist, Kevin</creatorcontrib><creatorcontrib>Haley, Henry</creatorcontrib><creatorcontrib>Bedi, Karan</creatorcontrib><creatorcontrib>Ljungman, Mats</creatorcontrib><creatorcontrib>Galbán, Craig J</creatorcontrib><creatorcontrib>Luker, Gary D</creatorcontrib><creatorcontrib>Dort, Marcian Van</creatorcontrib><creatorcontrib>Ross, Brian D</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Molecular cancer therapeutics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Galbán, Stefanie</au><au>Apfelbaum, April A</au><au>Espinoza, Carlos</au><au>Heist, Kevin</au><au>Haley, Henry</au><au>Bedi, Karan</au><au>Ljungman, Mats</au><au>Galbán, Craig J</au><au>Luker, Gary D</au><au>Dort, Marcian Van</au><au>Ross, Brian D</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A Bifunctional MAPK/PI3K Antagonist for Inhibition of Tumor Growth and Metastasis</atitle><jtitle>Molecular cancer therapeutics</jtitle><addtitle>Mol Cancer Ther</addtitle><date>2017-11-01</date><risdate>2017</risdate><volume>16</volume><issue>11</issue><spage>2340</spage><epage>2350</epage><pages>2340-2350</pages><issn>1535-7163</issn><eissn>1538-8514</eissn><abstract>Responses to targeted therapies frequently are brief, with patients relapsing with drug-resistant tumors. For oncogenic MEK and BRAF inhibition, drug resistance commonly occurs through activation of PI3K/AKT/mTOR signaling and immune checkpoint modulation, providing a robust molecular target for concomitant therapy. Here, we evaluated the efficacy of a bifunctional kinase inhibitor (ST-162) that concurrently targets MAPK and PI3K signaling pathways. Treatment with ST-162 produced regression of mutant KRAS- or BRAF-addicted xenograft models of colorectal cancer and melanoma and stasis of BRAF/PTEN-mutant melanomas. Combining ST-162 with immune checkpoint blockers further increased efficacy in a syngeneic KRAS-mutant colorectal cancer model. Nascent transcriptome analysis revealed a unique gene set regulated by ST-162 related to melanoma metastasis. Subsequent mouse studies revealed ST-162 was a potent inhibitor of melanoma metastasis to the liver. These findings highlight the significant potential of a single molecule with multikinase activity to achieve tumor control, overcome resistance, and prevent metastases through modulation of interconnected cell signaling pathways.
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| source | American Association for Cancer Research; EZB-FREE-00999 freely available EZB journals |
| subjects | 1-Phosphatidylinositol 3-kinase AKT protein Animal models Cancer Colorectal cancer Colorectal carcinoma Drug resistance Enzyme inhibitors Gene expression Immune checkpoint Inhibition Inhibitors K-Ras protein Kinases Liver MAP kinase Melanoma Metastases Metastasis Modulation PTEN protein Regression analysis Signal transduction Signaling TOR protein Tumors Xenografts |
| title | A Bifunctional MAPK/PI3K Antagonist for Inhibition of Tumor Growth and Metastasis |
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